Diversity and complexity of cardiac sodium channel (dys)function Relevance for arrhythmias in inherited and acquired diseases

The cardiac sodium channel Na_V1.5 plays a major role in the initiation of the cardiac action potential and propagation of the electrical impulse in the heart. Dysfunction of Na_V1.5, caused by inherited mutations in SCN5A (the gene encoding Na_V1.5), or acquired diseases (such as myocardial ischemia and heart failure), is associated with a diversity of cardiac electrical disorders and sudden cardiac death. In the past decades, genetic, electrophysiological and molecular studies have significantly advanced our understanding of Na_V1.5 (dys)function and its role in cardiac electrophysiology and arrhythmogenesis. However, the diverse and heterogeneous clinical phenotypes associated with Na_V1.5 (dys)function remain incompletely understood, which hampers identification of patients at risk for sudden cardiac death and their clinical management. The work presented in this thesis is centered on the hypothesis that sodium channel functions are diverse and extend beyond the generation of an action potential. We thus studied the consequences of inherited sodium channel (dys)function on sodium and calcium homeostasis, the modulatory effect of hypertension on arrhythmia susceptibility, sudden cardiac death and (atrio-)ventricular conduction in inherited sodium channelopathy and the microdomain-specific remodeling of Na_V1.5 in heart failure. Novel insight presented in this thesis will facilitate future development of new risk stratification and therapeutic strategies for patients with sodium channel disease.